1. clinicaloptions.com/oncology FRANCESCO BOCCARDO Professore Ordinario di Oncologia Medica, Università di Genova Direttore Oncologia Medica B IST.Genova Presidente Nazionale Associazione Italiana Oncologia Medica Presidente Nazionale Associazione Italiana Oncologia Medica INIBITORI DELL’AROMATASI (back from San Antonio)

2. clinicaloptions.com/oncology Initial diagnosis2-3 years after Tam or AI 5 years after Tam or AI Beyond 10 years? Tamoxifen Aromatase inhibitor 5 years total10 years total> 10 years Decision Points ? ? ? ? ? 1 2 3 4 4 ? 3

3. Initial diagnosis2-3 years after Tam 5 years after Tam or AI More Tamoxifen Aromatase inhibitor 5 years total10 years total> 10 years Decision Points:after 2-3 yrs of Tam ? ? IES ABCSG8/ARNO95 ITA 1

4. The Lancet 9561:533-5, 2007

7. clinicaloptions.com/oncology AIOG Metanalysis

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11. ……….back from San Antonio 2008: take home #1 “There is a clear benefit (including a S benefit) in switching women already on treatment with Tam to an AI (anastrozole,exemestane) unless AI therapy is contraindicated”

12. Decision Points: Initial choice ? ? ? ? Initial diagnosis2-3 years after Tam 5 years after Tam or AI Beyond 10 years? Tamoxifen Aromatase inhibitor 5 years total10 years total> 10 years ATAC BIG 1-98 monotherapy TEAM 2.75 yr ? 2

13. ATAC:100 mos median follow-up, Lancet Oncology 2007

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15. AIOG Metanalysis

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19. : TEAM trial

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22. ……….back from San Antonio 2008: take home #2 Which drug or which patients?”

23. Predicting the benefit and the risks. Tamoxifen vs Ais: Tumor Profile –ERPgR –HER2 –Recurrence Score –Cyclin E –uPA/uPAI-1 –Bcl-2 –ER-beta Patient Profile –Osteoporosis –Hypercholesterolemia –CV risk factors –Endometrial pathologies –DVT & TE risk factors –SSRI use –CYP 19 Genotype –CYP2D6 Genotype

24. clinicaloptions.com/oncology TRANSACT

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27. ABCSG 8

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31. ……….back from San Antonio 2008: take home #3 Starting with an Ai is a reasonable choice especially in certain patient subsets (i.e. PgRneg,HER2 pos,HRScore Node neg,poor metabolizers of CYP2D6….!):however: 1) no major survival advantge yet 2) No over rate in selecting patients

32. clinicaloptions.com/oncology Initial diagnosis2-3 years after Tam or AI 5 years after Tam or AI Beyond 10 years? Tamoxifen Aromatase inhibitor 5 years total10 years total> 10 years Decision Points:sequencing ? ? ? ? ? 1 2 3 4 4 ? 3 ABCSG8 TEAM 5-yr: n.a. yet BIG-1-98

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37. 1849+1865-792= 2922

38. clinicaloptions.com/oncology Actually received treatment

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40. Actually received treatment

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43. Sequencing versus LTZ

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48. Take home #3

49. Primary surgery RandomizeRandomize LTZ/ANA (3 years) Switching period Sequencing period Switch point Examestane (3 years) LTZ/ANA (2 years) LTZ/ANA (2 years) DOUBLE TRIAL

50. ……….back from S. Antonio 2008: Take home #4 “sequencing TAM with an Ai is better than TAM alone,but it does not offer major advantages vs Ai alone; switching from an Ai to TAM is possible if required… “

51. Initial diagnosis2-3 years after Tam 5 years after Tam or AI More Tamoxifen Aromatase inhibitor 5 years total10 years total> 10 years Decision Points:after 5 yrs of Tam MA.17 ABCSG6a NSABP B-42 ? ? NSABP B-14

52. DFS Years OS Years  Tamoxifen demonstrated higher rates of endometrial cancer, and more deaths from ischemic heart disease and cerebrovascular disease 100 90 80 70 60 50 Percentage of Patients 05 Placebo Tamoxifen 7 82% 78% P =.03 1246305 100 90 80 70 60 50 7 Percentage of Patients Placebo Tamoxifen 94% 91% P =.07 13246 Fisher B, et al. J Natl Cancer Inst. 2001;93:684-690. NSABP B-14: No Benefit of Extending Tamoxifen Beyond 5 Years

53. DFS* Distant* DFS Node* pos Node* neg Node neg Node* pos *non statistically significant HR: 0.61 (0.45-0.84) HR: 0.45 (0.27-0.75) HR: 0.63 (0.31-1.27) HR: 0.53 (0.36-0.78) HR: 1.52 (0.76-3.06) HR: 0.61 (0.38-0.98) HR: 0.58 (0.45-0.76) HR: 0.61 HR: 0.82 (0.57-1.19) OS Goss PE, et al. J Natl Cancer Inst. 2005;97:1262-1271.  Preplanned analysis (n = 5187) MA.17: Key Endpoints in Nodal Subgroups

54. Adjusted HR (PLAC-LET to PLAC) for Efficacy Outcomes :postumblinding Goss PE, et al. SABCS 2005. Abstract 16. p<0.000 1 p=0.002 p=0.05 p=0.012 0.31 0.28 0.53 0.23 0 0.1 0.2 0.3 0.4 0.5 0.6 PLAC-LET to PLAC Disease-free survivalDistant disease-free survival Overall survivalContralateral breast cancer Hazard Ratio P <.0001 P =.002 P =.05 P =.012

55. ………back from S.Antonio 2008: Take home #5 “ Late switching after 5 yrs of TAM: no news “

56. Initial diagnosis2-3 years after Tam 5 years after Tam or AI More Tamoxifen Aromatase inhibitor 5 years total10 years total> 10 years Decision Points:after 5 yrs of AIs MA.17 MA.17-R NSABP B-42 ? ? NSABP B-14

57. AI x 5 yrs AI x 3-2 yrs Tam x 2-3 yrs Letrozole x 5 yrs Placebo x 5 yrs Letrozole vs placebo after 5 years; not yet enrolling NSABP B-42: Study Design

58. Primary endpoint: DFS Secondary endpoints: OS, incidence of contralateral breast cancer, long-term clinical and laboratory safety, overall QoL, menopausal QoL MA.17R: Design Rerandomization (Disease-free) Letrozole Placebo qd Letrozole 2.5 mg qd 5 years’ early adjuvant5 years’ extended adjuvant

59. …….back from S. Antonio 2008: Take home #6 “ are trials concerning Ai optimal duration still prioritary? “

60. clinicaloptions.com/oncology ZO-FAST

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62. Immediate Therapy With Zoledronic Acid Prevents Bone Loss and Improves DFS in Women With Early Breast Cancer Receiving Letrozole Zometa-Femara Adjuvant Synergy Trial (ZO-FAST): 36-month follow-up results of multicenter, randomized phase III trial[1]

63. …….back from S. Antonio 2008: Take home #7 “ the seed and soil theory likely to work: data from ABCSG 12 confirmed!”

64. EARLY SWITCHING : 1) the new standard for the patients already on treatment with TAM from 2 or 3 yrs 2) switching from LTZ to TAM after 2-3 yrs possible if required LATE SWITCHING : a reasonable option for patients at the completion of 5 yrs of TAM, namely for N pos (no news from San Antonio) UPFRONT : the choice for the patients who have contraindications to the use of TAM. A reasonable choice for the patients at higher risk of relapse (HR score) or for whom a suboptimal response to TAM might be predicted (CYPD26) : cost/benefit to be defined in the individual patient (no S advantage on the average) SEQUENCING : 1) no better /no worse than LTZ 2) evidence of a significant benefit in respect to TAM alone AIs IN THE ADJUVANT SETTING,back from San Antonio 2008:

65. ………back from S.Antonio 2008: Take home #8 “ THANK YOU! ”